sotorasib in previously treated locally advanced or metastatic nsclc subjects with mutated kras p.g12c

Conditions: KRAS P.G12C; Non Small Cell Lung Cancer

Summary: this study aims to provide a comprehensive understanding of sotorasib's mechanisms of action and resistance in nsclc patients.


Eligibility criteria:
inclusion criteria: * age higher than 18 years; * ecog less or equal to 1 at the time of screening; * pathologically documented, previously treated, locally-advanced and unresectable or metastatic nsclc with kras p.g12c mutation confirmed through molecular testing (results of both tissue and liquid biopsy are accepted); * subjects will have progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease. * life expectancy of longer than 3 months from the time of screening, in the opinion of the investigator; * patients must have lesions easily accessible to biopsy and must have accepted to perform pre-treatment, on-treatment and end-of-treatment biopsies; * have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to registration * patients must understand, sign and date the written informed consent from prior to any protocol-specific procedures performed. * patients should be able and willing to comply with study visits and procedures as per protocol. * patients must be affiliated to a social security system or beneficiary of the same. exclusion criteria: * patient unwilling to participate to the biological investigations and to perform biopsies and blood sample collection as required in the protocol; * use of known cytochrome p450 (cyp) 3a4 or p-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to registration, that was not reviewed and approved by the principal investigator. * use of strong inducers of cyp3a4 (including herbal supplements such as st. john's wort) within 14 days or 5 half-lives (whichever is longer) prior to registration, that was not reviewed and approved by the principal investigator. * inadequate washout period prior to registration, defined as: any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study shorter than 14 days or 5 half-lives; * prior treatment with a kras inhibitor. * major surgery within 28 days of registration. * significant gastrointestinal disorder that results in significant malabsorption, requirement for intravenous alimentation, or inability to take oral medication. * significant cardiovascular disease, such as new york heart association cardiac disease (class ii or greater), myocardial infarction within 6 months prior to registration, unstable arrhythmias or unstable angina. * severe infections within 2 weeks prior to registration, but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia. prophylactic antibiotics are allowed. * baseline or unresolved pneumonitis from prior treatment; * current ctcae version 5.0 grade higher or equal to 2 peripheral neuropathy. * uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures at a frequency greater than monthly. subjects with pleurx catheters in place may be considered for the study with principal investigator approval. * known history of human immunodeficiency virus (hiv) infection * exclusion of hepatitis infection based on the following results and/or criteria: 1. positive hepatitis b surface antigen (hepbsag) (indicative of chronic hepatitis b or recent acute hepatitis b) 2. negative hepbsag with a positive for hepatitis b core antibody (hepatitis b core antibody testing is not required for screening, however if this is done and is positive, then hepatitis b surface antibody \[anti-hbs\] testing is necessary. undetectable anti-hbs in this setting would suggest unclear and possible infection, and needs exclusion). 3. positive hepatitis c virus antibody: hepatitis c virus rna by polymerase chain reaction is necessary. detectable hepatitis c virus rna renders the subject ineligible. * leptomeningeal disease and active brain metastases. subjects who have had brain metastases resected or have received whole brain radiation therapy or stereotactic radiosurgery ending at least 2 weeks prior to registration are eligible if they meet all of the following criteria: 1. residual neurological symptoms grade less or equal to 2; 2. on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and 3. follow-up brain imaging performed within 30 days of enrollment shows no progression or new lesions appearing. * female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib or during treatment if planning to become pregnant. * female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib * female subjects of childbearing potential with a positive pregnancy test assessed at screening or day 1 by a serum pregnancy test and/or urine pregnancy test. * male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 7 days after the last dose of sotorasib * male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for an additional 7 days after the last dose of sotorasib * male subjects unwilling to abstain from donating sperm during treatment and for an additional 7 days after the last dose of investigational product. * any evidence of primary malignancy other than locally advanced or metastatic lung cancer at within 3 years of registration, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated; * participation in another clinical trial evaluating an experimental drug (except non-interventional research). * patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent. * hypersensitivity to the active substance or to any excipient * patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption